DOWN-REGULATION OF beta1-ADRENOCEPTORS IN RAPID PACING-INDUCED HEART FAILURE IN DOGS WITH LEFT VENTRICULAR HYPERTROPHY

Tse, James; Weiss, HR; He, Yong; Scholz, PM

doi:10.1097/00000539-199804001-00039

Cited by 9 publications

(16 citation statements)

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“…In the dog model of rapid pacing-induced heart failure, a reduction of myocardial particulate PDE3A gene expression and activity was observed while cytosolic PDE3 activity was not changed [37,175,189]. Importantly, cAMP PDE activity in this heart failure model was subjected to regional changes as evidenced by reduced rate of cAMP elimination found in left ventricular subendocardium with no changes determined in the epicardium [175].…”

Section: Myocardial Phosphodiesterase Activitymentioning

confidence: 79%

“…No changes in myocardial low K m cAMP PDE activity were found in pressure-overload cardiac hypertrophy induced by aortic stenosis in dogs [36,189]. However, pressure-overload cardiac hypertrophy and heart failure were associated with an increased cardiac expression and activity of PDE3 and PDE4 in Dahl salt-sensitive rats, an effect associated with reduced myocardial cAMP concentrations [190].…”

Section: Myocardial Phosphodiesterase Activitymentioning

confidence: 98%

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Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Osadchii

2007

Cardiovasc Drugs Ther

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Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of I (Ca2+) which ultimately results in increased Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. A number of additional effects such as increases in sarcoplasmic reticulum Ca(2+) stores, stimulation of reverse mode Na(+)-Ca(2+) exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca(2+) release mechanism, as well as A(1) adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca(2+) sensitizer properties as they could increase the affinity of troponin C Ca(2+)-binding sites as well as reduce Ca(2+) threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from beta-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and beta-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.

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Section: Myocardial Phosphodiesterase Activitymentioning

confidence: 79%

Section: Myocardial Phosphodiesterase Activitymentioning

confidence: 98%

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Osadchii

2007

Cardiovasc Drugs Ther

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“…Chronic adrenoceptor activation is accompanied by a reduction in the number of ␤ 1 -AR [18,19] . In patients with dilated cardiomyopathy, the beta-adrenergic responsiveness of the myocardium is diminished.…”

Section: Discussionmentioning

confidence: 99%

Effects of Beta-Adrenoceptors Overexpression on Cell Survival Are Mediated by Bax/Bcl-2 Pathway in Rat Cardiac Myocytes

et al. 2006

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Background: Chronic activation of β-adrenoceptors (β-ARs) results in cardiac myocyte injury, even death, and diminishes the number of β-ARs. Objectives: To investigate the effects of overexpression of β₁- or β₂-AR on cardiomyocytes injured by isoprenaline (ISO). Methods: We have used an adenoviral vector carrying the sequence for human β₁- or β₂-AR (Adv.β₁, Adv.β₂) to increase the content of β₁ or β₂-AR in isolated adult rat ventricular myocytes, and we have examined the cell survival and the expression of Bax and Bcl-2. Results: With use of adenoviral vectors, the β₁- and β₂-AR contents of myocytes were increased 2.98- and 2.87-fold, respectively. Overexpression of β₁-AR sharpened the cellular injury of ISO. If β₂-AR activity was further blocked by addition of selective β₂-AR antagonist ICI118,551, the cells were more sensitive to the impairment of Adv.β₁ + ISO. Overexpression of Adv.β₂ partially inversed the cytotoxicity of ISO stimulation. The beneficial effects were strengthened by addition of CGP20712A, a β₁-AR-blocking agent. Western blot analysis demonstrated that both increasing β₁-AR and inhibition of β₂-AR increased the ratio of Bax/Bcl-2. Whereas, increasing β₂-AR and inhibition of β₁-AR decreased the ratio of Bax/ Bcl-2. Control adenovirus CGP had no effect on cell survival. Conclusions: Overexpression of Adv.β₂ and/or inhibition of β₁-AR have protective effect on adult rat ventricular myocytes chronically stimulated by ISO. Overexpression of Adv.β₁ and/or inhibition of β₂-AR are deleterious in the same state. The effects of β-ARs on cell survival might be mediated by the Bax/Bcl-2 signal pathway.

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“…First, whether the effects of carvedilol on dogs are comparable to the effects of this drug on humans is not known. Second, in dogs with heart failure, β-receptors are down-regulated [6,13,24] and intracellular cAMP concentrations are reduced [17,19]. Therefore, the responses of animals with heart failure to β-receptor agonists and PDE III inhibitors may differ from those of healthy animals.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

Uechi

Hori

Fujimoto

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study was to determine whether dobutamine, dopamine, or milrinone (a phosphodiesterase [PDE] III inhibitor) would support cardiac function that had been attenuated by administration of the β-blocker, carvedilol (0.2, 0.4, or 0.8 mg/kg). Hemodynamic and cardiac parameters including the heart rate (HR), left-ventricular fractional shortening (FS), and arterial pressure were measured in six healthy dogs without cardiac disease. Carvedilol did not affect FS or arterial pressure, but decreased the HR significantly. The positive inotropic and chronotropic responses to dobutamine and dopamine were attenuated by carvedilol, whereas arterial pressure was unaffected. Milrinone did not affect the HR and decreased arterial pressure, whereas FS was significantly greater both in the control and carvedilol-treated groups. Although milrinone affect the negative chronotropic effects of carvedilol, milrinone increased FS and prevented the decrease in arterial pressure. These results suggest that inhibition of PDE III preserves cardiac contractility and hemodynamic function in the presence of carvedilol.KEY WORDS: β-blocker, cardiac function, heart failure, inotropic agent.J. Vet. Med. Sci. 68(6): 549-553, 2006 Clinical studies on humans have shown that treatment of congestive heart failure with β-blockers can reduce mortality [4,5,10,16] by improving myocardial energy metabolism, reducing arrhythmia, reducing damage to cardiac myocytes, up-regulating β 1 receptor expression, and improving diastolic function [5]. However, cardiac function must be monitored carefully in heart failure patients who are undergoing treatment with β-blockers because such treatment is associated with side effects that include bradycardia, hypotension, and A-V node blocking [2,21].It has been established that sympathomimetic drugs such as dobutamine and dopamine may prevent acute heart failure and circulatory collapse. However, the down-regulation of myocardial β-receptors that occurs during heart failure leads to an attenuation of the chronotropic and inotropic effects of β-receptor agonists such as adrenaline, noradrenaline, dobutamine, and dopamine [3,7,9]. Milrinone, an inhibitor of phosphodiesterase (PDE) III, increases the concentration of intracellular cyclic adenosine monophosphate (cAMP) by retarding the degradation of this molecule [1,22]. The modulation of intracellular cAMP by milrinone produces inotropic and chronotropic effects on the heart and relaxation of vessels in the absence of β-receptor stimulation [1,12,23]. Therefore, milrinone may produce beneficial effects even though myocardial β-receptors are downregulated during heart failure. Presumably, the beneficial effects of milrinone also apply in situations in which β-receptors have been blocked by the administration of a β-The objective of this study was to determine whether dobutamine, dopamine, or milrinone could support cardiac function that had been attenuated by the administration of a β-blocker. To achieve the objective, the hemodynamic and cardia...

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DOWN-REGULATION OF beta1-ADRENOCEPTORS IN RAPID PACING-INDUCED HEART FAILURE IN DOGS WITH LEFT VENTRICULAR HYPERTROPHY

Cited by 9 publications

References 0 publications

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Effects of Beta-Adrenoceptors Overexpression on Cell Survival Are Mediated by Bax/Bcl-2 Pathway in Rat Cardiac Myocytes

Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

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